title: Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance.
abstract: Aminoglycosides are a class of antibiotics with a broad spectrum of antimicrobial activity. Unfortunately, resistance in clinical isolates is pervasive, rendering many aminoglycosides ineffective. The most widely disseminated means of resistance to this class of antibiotics is inactivation of the drug by aminoglycoside-modifying enzymes (AMEs). There are two principal strategies to overcoming the effects of AMEs. The first approach involves the design of novel aminoglycosides that can evade modification. Although this strategy has yielded a number of superior aminoglycoside variants, their efficacy cannot be sustained in the long term. The second approach entails the development of molecules that interfere with the mechanism of AMEs such that the activity of aminoglycosides is preserved. Although such a molecule has yet to enter clinical development, the search for AME inhibitors has been greatly facilitated by the wealth of structural information amassed in recent years. In particular, aminoglycoside phosphotransferases or kinases (APHs) have been studied extensively and crystal structures of a number of APHs with diverse regiospecificity and substrate specificity have been elucidated. In this review, we present a comprehensive overview of the available APH structures and recent progress in APH inhibitor development, with a focus on the structure-guided strategies.
authors.affiliation: Groupe de Recherche Axé sur la Structure des Protéines, Department of Biochemistry, McGill University Montreal, QC, Canada.
authors.forename: Kun
authors.initials: K
authors.lastname: Shi
authors.forename: Shane J
authors.initials: SJ
authors.lastname: Caldwell
authors.forename: Desiree H
authors.initials: DH
authors.lastname: Fong
authors.forename: Albert M
authors.initials: AM
authors.lastname: Berghuis
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D055808:Drug Discovery / Q000379:methods; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000378:metabolism; D019868:Kanamycin Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D019868:Kanamycin Kinase
keywords: aminoglycosides; antibiotic resistance; drug design; inhibitor; kinases; structure-based